Glucocorticoids are steroid hormones that regulate many metabolic and homeostatic processes, including fat metabolism, function and distribution. Glucocorticoids also have profound and diverse physiological effects on development, neurobiology, inflammation, blood pressure, metabolism and programmed cell death.
Glucocorticoid action is dependent on the following factors: 1) circulating levels of glucocorticoid; 2) protein binding of glucocorticoids in circulation; 3) intracellular receptor density inside target tissues; and 4) tissue-specific pre-receptor metabolism by glucocorticoid-activating and glucocorticoid-inactivating enzymes collectively known as 11-beta-hydroxysteroid dehydrogenase (11-β-HSD). Two distinct isozymes of 11-β-HSD have been cloned and characterized. These two isozymes, known as 11-β-HSD type I and 11-β-HSD type II, respectively, catalyze the interconversion of active and inactive forms of various glucocorticoids. For example, in humans, the primary endogenously-produced glucocorticoid is cortisol. 11-β-HSD type I and 11-β-HSD type II catalyze the interconversion of hormonally active cortisol and inactive cortisone. 11-β-HSD type I is widely distributed in human tissues and its expression has been detected in lung, testis, central nervous system and most abundantly in liver and adipose tissue. Conversely, 11-β-HSD type II expression is found mainly in kidney, placenta, colon and salivary gland tissue.
Up-regulation of 11-β-HSD type I can lead to elevated cellular glucocorticoid levels and amplified glucocorticoid activity. This, in turn, can lead to increased hepatic glucose production, adipocyte differentiation and insulin resistance. In type II diabetes, insulin resistance is a significant pathogenic factor in the development of hyperglycemia. Persistent or uncontrolled hyperglycemia in both type 1 and type 2 diabetes has been associated with increased incidence of macrovascular and/or microvascular complications including atherosclerosis, coronary heart disease, peripheral vascular disease, stroke, nephropathy, neuropathy and retinopathy. Insulin resistance, even in the absence of profound hyperglycemia, is a component also of metabolic syndrome, which is characterized by elevated blood pressure, high fasting blood glucose levels, abdominal obesity, increased triglyceride levels and/or decreased HDL cholesterol. Further, glucocorticoids are known to inhibit the glucose-stimulated secretion of insulin from pancreatic beta-cells. Inhibition of 11-β-HSD type I is, therefore, expected to be beneficial in the treatment of metabolic syndromes, obesity, obesity-related disorders, hypertension, atherosclerosis, lipid disorders, type-II diabetes, insulin resistance, pancreatitis and associated conditions.
Mild cognitive impairment is a common feature of aging that may be ultimately related to the progression of dementia. Chronic exposure to glucocorticoid excess in certain brain subregions has been proposed to contribute to the decline of cognitive function. Inhibition of 11-β-HSD type I is expected to reduce exposure to glucocorticoids in the brain and protect against deleterious glucocorticoid effects on neuronal function, including cognitive impairment, dementia and/or depression, especially in connection with Alzheimer's Disease.
Glucocorticoids also have a role in corticosteroid-induced glaucoma. This particular pathology is characterized by a significant increase in intra-ocular pressure, which unresolved can lead to partial visual field loss and eventually blindness. Inhibition of 11-β-HSD type I is expected to reduce local glucocorticoid concentrations and, thus, intra-ocular pressure, producing beneficial effects in the management of glaucoma and other visual disorders.
Finally, glucocorticoids can have adverse effects on skeletal tissues. Continued exposure to excess glucocorticoids can produce osteoporosis and increased risk of fractures. Inhibition of 11-β-HSD type I should reduce local glucocorticoid concentration within osteoblasts and osteoclasts, producing beneficial effects for management of bone disease, including osteoporosis.
In view of the foregoing, there is a clear and continuing need for new compounds that target 11-β-HSD type I.